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CN101111221A - Use of morpholine compounds in preventing bacterial contamination - Google Patents

Use of morpholine compounds in preventing bacterial contamination Download PDF

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Publication number
CN101111221A
CN101111221A CNA2006800037141A CN200680003714A CN101111221A CN 101111221 A CN101111221 A CN 101111221A CN A2006800037141 A CNA2006800037141 A CN A2006800037141A CN 200680003714 A CN200680003714 A CN 200680003714A CN 101111221 A CN101111221 A CN 101111221A
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Prior art keywords
compound
medical device
biofilm
chemical compound
delmopinol
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CNA2006800037141A
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CN101111221B (en
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J·莱恩
O·T·斯乔丁
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Boehringer Ingelheim Animal Health USA Inc
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Sinclair Pharmaceuticals Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • A—HUMAN NECESSITIES
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    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/08—Amines; Quaternary ammonium compounds containing oxygen or sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive bandages or dressings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]

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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

A compound of formula I: wherein R1 is a straight or branched alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholino ring, and R2 is a straight or branched alkyl group containing 2 to 10 carbon atoms, substituted with a hydroxy group except in the alpha-position, the sum of the carbon atoms in the groups R1 and R2 being at least 10 and preferably 10 to 20, is used to prevent biofilm formation on a surface. The compounds are particularly useful as coatings or treatments for medical devices, including stents, catheters and wire guides.

Description

The purposes of morpholinium compound in preventing germ contamination
Technical field
The present invention relates to prevent at armarium and contain on the fluidic stored prod form biofilm.
Background technology
Biofilm simply be described as " be embedded in the organic polymer matrix, be attached to the surface microbiologic population " (Carpentier, 1993.J.Appl.Bacteriol.75:499-511).All biofilms all contain three kinds of bases: microorganism, glycocalyx and surface.If remove this one of them component, then biofilm can not further develop.
Biofilm can be formed by a kind of bacteria culture, but biofilm is made up of various bacteria strain and fungus, algae, protozoacide, fragment and corrosion product usually.Biofilm can almost form on any surface that is exposed to antibacterial and certain water gaging.
Bacterial adhesion in suitable (biological or abiotic) surface and the process that develops biofilm subsequently by W.Michael Dunne Jr, Clin Microbiol Rev.2002Apr; 15 (2): 155-66 summarizes.Adhering to of antibacterial, comprise bacteria culture, surface composition, envirment factor and main gene outcome by a plurality of parameter decisions.
In brief, biofilm bacterial adhesion in water environment the surface and form when beginning to secrete the colloid substance that has viscosity, this colloid substance can be anchored on it on a series of materials such as metal, plastics, soil particle, medical implant material and the tissue etc.
Initial adherence occurs by qualified surface (conditioned surface) and the encounter of plankton.Further summarize, the initial adherence on antibacterial and abiotic surface is subjected to non-specific (as hydrophobicity) interaction mediation, and finishes by specific molecular (agglutinin, part or adhesin) berthing mechanism with the adhesion of living tissue or devitalized tissue.This stage is reversible, is determined by limiting bacterial cell surface and the qualified interactional the physical-chemical parameters of studying between the surface.
After the initial adherence, the grappling stage can occur, wherein adhere to by producing, irreversibly be attached to this surface thus with the exopolysaccharide consolidation of surface combination in conjunction with loose biology.
In case antibacterial irreversibly adheres to, then begin to enter the period of maturation of biofilm.Because the biology of surface combination duplicates (and dead) actively, and the organic and inorganic molecule in the outer component of (being produced by particle-bound bacteria) born of the same parents and the adjacent ambient interacts and formed glycocalyx, so the total body density of biofilm and complexity rising.Exopolysaccharide has formed the key component of glycocalyx (outside dewatering), and the glycocalyx in most of strain mainly is an anionic property, can also catch nutrient and protect antibacterial to avoid environmental injury.With regard to infected biologic medical implant, glycocalyx can comprise and is attached to inflammatory response albumen implant, that derive from the host or stromatin such as complement, fibrinogen and Portugal's amine polysaccharide etc.
The growth potential of biofilm is subject to the availability, these nutrients of nutrient in the adjacent ambient to the perfusion of biofilm inner cell and removing of refuse.The fluid with best hydrodynamics that flows through biofilm helps outermost growth and perfusion but not corrodes.The sophisticated other factors of regulation and control biofilm comprises internal pH, oxygen perfusion, carbon source and permeability.Reach dynamic equilibrium when critical mass, at this moment, the outermost layer of growth (apart from the surface farthest) has formed plankton.These biologies can freely break away from biofilm and settle down on other surface.Owing to lack nutrient or perfusion, pH decline, pO 2The accumulation of decline or toxic metabolite by-product, the nearest cell in distance surface begins dormancy or death.
In case be anchored into the surface, the biofilm microorganism is carried out multiple harmful or useful reaction (according to the mankind's standard) according to environmental condition on every side.The surface microorganism biofilm is expending multi-million dollar aspect device damage, contamination of products, energy loss and the medical science infection every year.The conventional method (as antibiotic and sterilization) of killing and wounding antibacterial is invalid for the biofilm antibacterial usually, and this part is because the protectiveness of glycocalyx.Remove the required not environmental protection of a large amount of antimicrobial of biofilm bacterial system (and may not allowed by environmental legislation) and medically also impracticable (reason is to kill and wound the required amount of biofilm antibacterial also has side effect to the patient).
Although to the surface that hinders bacterial adhesion or the pan coating thing is existing describes (Sheng etal for example, Diagn.Microbiol.Infect.Dis.38:1-5), do not prevent this surface of adhering to or pan coating thing (p1-11 but develop, Lappin-Scott and Costerton, Microbial Biofilms 1995.Cambridge University Press).Therefore, needing new method to control biofilm forms.
Summary of the invention
The present invention is based on such understanding: delmopinol (delmopinol) and derivant thereof can be used to prevent or reduce the formation of biofilm or guarantee that biofilm is in avirulence (nonactive) state.This may be used on industrial, comprises that preventing that biofilm from storing or sending on the delivery apparatus at surgical device or water forms.
According to a first aspect of the invention, the compound or its salt with formula (I) can be used to prevent or reduces biofilm form on the surface, and perhaps prevent or reduce viable microbial in superficial growth,
Figure A20068000371400061
R wherein 1Be the straight or branched alkyl that contains 8 to 16 carbon atoms that is positioned at morpholine ring 2-or 3-position, R 2Be the straight or branched alkyl that contains 2 to 10 carbon atoms, replaced radicals R in the position except that the α position by hydroxyl 1And R 2The carbon number summation be at least 10, be preferably 10 to 20.
According to a second aspect of the invention, above-claimed cpd is used for handling the purposes of surgical instrument between surgical operation.
According to a third aspect of the invention we, the swab that is flooded by above-claimed cpd.
According to a forth aspect of the invention, be coated with the armarium of above-claimed cpd.
According to a fifth aspect of the invention, be coated with filter, water-supply-pipe or the fluid storage groove of above-claimed cpd.
According to a sixth aspect of the invention, the container that comprises above-claimed cpd is used for treatment surface and forms biofilm to prevent or to reduce on described surface, or prevents or reduce viable microbial and grow on described surface.
According to a seventh aspect of the invention, container contains and a plurality ofly independently packs, and each packing contains the above-claimed cpd of unit dosage forms liquid form.
The specific embodiment
The present invention is based on so amazing discovery: delmopinol and derivant thereof can prevent or reduce biofilm formation and/or can guarantee any bacterial biofilm non-activity, promptly are in non-existing state.Term as used herein " biofilm " refers to this term art-recognized meanings in this area, promptly is attached to the microbiologic population and the relevant glycocalyx on surface.There are a plurality of definition in this area, and this each definition wherein all within the scope of the invention.For example, Carpentier (referring to above) biofilm is described as " be embedded in the organic polymer matrix, be attached to the surface microbiologic population "; Costerton (1999 Science 284:1318-1322) is described as biofilm " being surrounded and adhere to the structuring bacterial cell group of inertia or active surface by the polymeric matrices that self produces "; Elder (1995Eye 9:102-109) is described as biofilm " accumulating in the functional consor body of the intramatrical microorganism of a large amount of extracellular polymerics (exopolymer) " with the term of more cooperation.
Be used for chemical compound of the present invention and have above-mentioned general formula (I), wherein R 1Be the straight or branched alkyl that closes 8 to 16 carbon atoms that is positioned at morpholine ring 2-or 3-position, R 2Be the straight or branched alkyl that contains 2 to 10 carbon atoms, replaced radicals R in the position except that the α position by hydroxyl 1And R 2The carbon number summation be at least 10, be preferably 10 to 20.In a preferred embodiment, described chemical compound is a delmopinol, i.e. 3-(4-propyl group-heptyl)-4-(2-ethoxy) morpholine, a kind of compound known.
The preparation method that is used for chemical compound of the present invention is described in US 4894221, and its content is included this paper in by quoting.
Mention " preventing from or reduce biofilm to form " in the following description.But the present invention comprises that also treatment surface is to prevent or to reduce the formation of " activity " biofilm.The active bio tunicle is for being the biofilm of feature with the viable microbial.Therefore, mention when preventing that biofilm from forming, comprise preventing or reducing the formation of viable microbial complex or colony or reduce the formation of this class complex or colony." minimizing " can measure by comparing with untreatment surface.
This chemical compound can be used to handle any surface.In fact, any surface---animal, mineral or plant (promptly biological or abiotic)---all may be fit to bacterial colonisation and biofilm and form, and comprises contact lens, hull, milk product and petroleum pipeline and all the biologic medical implant and the transcutaneous device of classifications; Therefore, this chemical compound can be used to prevent that biofilm from forming on this any surface wherein.
This chemical compound prevent from armarium to form aspect the biofilm useful especially, described armarium is surgical implants for example, comprise artificial joint such as hip joint, orthomorphia utensil such as pin, Pan Hexian, AFL/artificial limb, cardiac valve, support, contact lens and be used to send the equipment of passing fluid, nutrient and medicine or being used to remove fluid and refuse, as conduit.For avoiding difference, term that this paper uses " armarium " comprises employed equipment of beauty method and implant.This chemical compound also can be used to prevent to form biofilm on the identification label of implanting the experimenter and information labels or electronic chip.
Chemical compound of the present invention also can be used to handle surgical instrument such as surgical knife, saw, dissecting knife, tweezers etc., or is used for operating any other utensil of invasive.
Armarium can be implant, promptly inserts the intravital equipment of experimenter.In a preferred embodiment, this equipment is surgical implants, and this implant need be carried out otch to health and be implanted.In an especially preferred embodiment, pending device is a dental implant, as the tooth pin or the tooth screw of fixing teeth.Perhaps, armarium contacts with health but does not enter health, as artificial limb, plaster cast, contact lens or external sonifer.
With regard to contact lens, chemical compound of the present invention can be impregnated into the surface of this contact lens.Perhaps, with regard to the aquogel type contact lens, this chemical compound can be impregnated in the hydrogel matrix.Perhaps, this chemical compound can be present in be used for preserving or the solution of cleaning contact lenses in.
The experimenter of implantation equipment (or contacting with it) can be the human or animal, and promptly veterinary applications also within the scope of the present invention.
This chemical compound is coated on the pending surface or equipment usually.There are a lot of methods this chemical compound can be coated on the suitable material, comprise and spray coating, radiation and ultra-violet curing.Improve with the technology of biomaterial coating medical equipment is now existing, and these technology may be used on the present invention.Therefore, the present invention includes coated material, particularly be coated with the armarium of the chemical compound of formula I.Because the fluid storage or the fluid that are coated with the filter of formula I chemical compound or water-supply-pipe and are through applying send delivery apparatus, therefore also within the scope of the invention.Material to be coated can be metal, plastics, pottery, polystyrene or glass.Preferably, material to be coated is metal such as rustless steel.
Chemical compound of the present invention can combine with processed surface by covalent bond or non-covalent bond connection.If with the covalent manner combination, then use link molecule that this chemical compound is connected to this surface.For example, Polyethylene Glycol (PEG) is for can be used for useful connection substrate of the present invention.Amination also can be used to provide effective link molecule.
Perhaps, this chemical compound can flood to substrate such as polymeric matrix.Conventional bioavailable polymer substrate can be used to this chemical compound is retained on this surface.For example, poly (organo) phophazene, hydrophilic hydrogel (as 2-hydroxyethyl methacry-late, HEMA) or silica-based applicator (as fluorosilicone) be all as the conventional applicator on the armarium, and can be used to keep chemical compound of the present invention.Suitable painting method is disclosed in US2005/0187611, and its content is included this paper in by quoting.
In a preferred embodiment, armarium in being inserted into the subject of implant to be placed or with experimenter's (body surface), contact before or during contact with formula I chemical compound.More preferably, this equipment with before the experimenter contacts or during washed by this chemical compound.More preferably, contact with the experimenter immediately after the flushing, carry out drying subsequently and make this chemical compound be coated on this equipment.
The preferred embodiments of the invention comprise that a certain amount of suitable applied once that is contained in the container is to armarium or other surperficial formula I chemical compound.Preferably, inner surface of container, its interior environment and inclusions (as delmopinol) they are aseptic, i.e. sterilization, and do not contain pathogen substantially, therefore be suitable for medical science (or beauty treatment) operation as surgical operation.More preferably, outer surface also is aseptic.The container of any suitable receiving fluids all can use, and preferred container can be sealed.But preferred container is sterile sealing and pouch or the parcel that can cut off or tear when needed when producing.Preferably, pouch can be by flexible plastic or metal material preparation; Suitable pouch is known in the art.Other suitable containers comprises bottle, jar and the pipe of any material, and described material is preferably glass or plastics.In a preferred embodiment, container is the container of storage or cleaning contact lenses.The container size (being predetermined the dosage that is stored in chemical compound wherein thus) that is fit to different application is conspicuous for a person skilled in the art, and for example, the hip joint implant needs more substantial delmopinol than (standard) conduit.Whether preferred each container is " disposable use " all, promptly in a single day container is opened and used inclusions, then no matter used all inclusions all it to be discarded.This has the advantage with any possible minimum contamination.
Chemical compound of the present invention can be present in the container by any suitable concn.Generally speaking, compound concentrations be 0.01% (w/v) to 10% (w/v), preferred 0.1% (w/v) be to 5% (w/v), and most preferably 1% (w/v) to 3% (w/v) as 2% (w/v).This chemical compound generally is present in the aqueous solution, but also can use other any suitable solvent that comprises alcohol.
Formula I chemical compound can impregnated in and be used for and prevent on the surperficial contacted material that biofilm forms thereon.This material can be textile or non-textile.Textile material generally is used for wipe surfaces; The limiting examples of suitable textile material comprises swab, cloth, rag or mop.Textile material can comprise natural fiber (as Cotton Gossypii) or synthetic fibers (as nylon), or both combinations.In a preferred embodiment, impregnated material can be aseptic/sterilization " disposable use " material that is suitable for medical environment, as binder.Most preferably, this material provides in said vesse; This container can only contain this impregnated material, or contains the chemical compound (except the surface is contacted with impregnated material, perhaps the surface not being contacted with impregnated material) on this impregnated material and excessive suitable flushing surface.
Formula I chemical compound also can be used for other commercial Application, and fluid such as water will contact with the surface this moment.In a preferred embodiment, this chemical compound be used for preventing the water that comprises desalt or transportation system (comprising water-supply-pipe and cistern) or fluid send pass or stocking system in form biofilm.
In another preferred embodiment, surface self is applied or dipping by chemical compound of the present invention.This embodiment is specially adapted to and will stops the surface of longer a period of time in the fixed position, and for example above-mentioned armarium and water or fluid send delivery system.
Chemical compound can contact with pending surface in a usual manner.For example, can be that solution also contacts this solution with the surface with compound.
Chemical compound can be used to flushing or the above-mentioned surface of wiping.In a preferred embodiment, this chemical compound is sprayed to described surface.In this embodiment, chemical compound can be prepared in being fit to produce aerosol can, spray bottle or other like device of dripping mist that contains described chemical compound.This method can make this chemical compound contact with very big surface effectively.This method is for also effective especially for the surface of the bad processing of shape or fine surface such as contact lens contact.
Chemical compound can send with any suitable form that can obtain required effect and pass.But this chemical compound can be included in the controlled release preparation or be stored in the device of this chemical compound of controlled release.Controlled release preparation can use with above-mentioned any other embodiment, and for example controlled release preparation can flood to send to the surface or by sprinkling and pass.
The compounds of this invention can its salt any form use.Particularly, this chemical compound can be its hydrochlorate form (example hydrochloric acid delmopinol) or its in aqueous solution than the low solubility form.Even if after flushing, this chemical compound still can be retained in the surface of treatment facility like this.
Prevent that effectively the amount that biofilm forms from being conspicuous for a person skilled in the art, and can determine based on pending surface.
Following non-limiting examples will the present invention is described further.
Embodiment
Test surfaces
This research comprises following test material:
● surgery is with rustless steel 316 (being used for for example cardiac valve)
● titanium (being used for for example hip joint implant)
Can obtain the different materials of disk form, the diameter of disk is about 30mm, and thickness is about 1mm.Then these disks are placed Petri culture dish bottom.
Test compounds
The hydrochloric acid delmopinol is dissolved in the UHQ level water, and making its concentration is 20mg/mL (2%w/v).This solution that keeps in Dark Place under the room temperature is until use.
Handle test surfaces with delmopinol
Method A: the hydrochloric acid delmopinol aqueous solution with 2mL 2% is handled test surfaces, and at room temperature leaves standstill 15 minutes.Remove fully a not alcoholic solution with pipet.(10mM is pH7.2) with hole cleaning down three times to use the 4mL kaliumphosphate buffer then.Because the pKa of delmopinol is 7.1, most chemical compound all can change into alkali, and this alkali dissolubility in aqueous solution is very low, therefore will rest on the surface between flush period and can not washed off fully.
Method B: the hydrochloric acid delmopinol aqueous solution with 2mL 2% is handled test surfaces, and dried overnight.
Microorganism
Be separated to the fresh bacterial strain of staphylococcus epidermidis (Staphylococcus epidermidis) and in milk powder, preserve from skin at-80 ℃.Experimentize the previous day, antibacterial is transferred to blood agar and at 95%H 2And 5%CO 2In the gas in 37 ℃ of incubated overnight.Collect colony forming unit and it is suspended in 10mM kaliumphosphate buffer (pH7.2) from blood agar, making its optical density is 0.4 at 600nm, and these are corresponding about 10 years old 8Individual cell/mL.
Use alive/dead antibacterial vigor (Live/Dead BacterialViability) method (Molecular Probes according to the description of manufacturer, Inc.Eugene, OR, USA), by the antibacterial vigor (being expressed as vigor percentage ratio) of fluorescence microscope estimation bacterial suspension.Therefore, SYTO9 (1.5 μ L) and propidium iodide (1.5 μ L) are mixed with 1mL 10mM phosphate buffer (pH7.2).The a mixed liquor that is divided into 10 μ L is added 10 μ L cell suspending liquids, and at 1000 * fluorescence microscope (Leitz Aristoplan microscope, be furnished with Halogen light and 470-490nm laser optical filter) analyze the green living cells of representing, the red dead cell of representing down.
Under all situations, the vigor of cell culture is all greater than 95%.
The analysis of adherence method
The 4mL bacterial suspension is added in the coating and non-coating test surfaces that places the Petri culture dish.Allow cell adhere to 60 minutes at 37 ℃.By surface washing being removed not attached cell three times with 4mL buffer solution.Remove lip-deep whole liquid and use above-mentioned dyestuff SYTO 9 and propidium iodide to manifest and adhere to antibacterial.The five equilibrium mixed liquor of 10 μ L is added to the surface and hatches 10 minutes post analysis in lucifuge.Each disk is got 10 visuals field the micro-imaging of attached cell is analyzed.Catch image and it is used for the attached cell number in each visual field is averaged with the digital camera that is connected with microscope.Use mathematical routine MATLAB that the number and the living cells percentage ratio of attached cell are estimated.
Break away from analytic process
On the surface that applies delmopinol, prepare the attached cell group as mentioned above.For whether test cell breaks away from from the surface with delmopinol, available 2% water-soluble delmopinol is analyzed surface washing three times subsequently with fluorescence microscope.
I. the influence of delmopinol encrusting substance to adhering to
Use parallel bacterial isolates culture three times, and provided the meansigma methods of different number of times.The sum of attached cell (viable count and non-viable count) is shown in table 1.
Relatively delmopinol is applied or the adhesion condition on uncoated surface.Illustrate 2% hydrochloric acid delmopinol solution pretreatment or unpretreated given lip-deep cell number/mm 2
Table 1
Experiment numbers Rustless steel Titanium
Uncoated Apply Uncoated Apply
I 250 739 377 415
II 227 241 1070 110
III 332 273 703 95
Meansigma methods 270 418 717 207
II. the delmopinol encrusting substance is to the influence of antibacterial vigor
Handle with three parallel bacterial isolateses as mentioned above and in the meansigma methods of different number of times table 2 illustrate.
Relatively delmopinol applies or uncoated lip-deep antibacterial vigor situation.Illustrate the living cells percentage ratio on the given test surfaces.
Table 2
Experiment numbers Rustless steel Titanium
Uncoated Apply Uncoated Apply
I 83 10 69 5
II 28 0 43 11
III 63 17 67 11
Meansigma methods 58 9 60 9
III. handle and the growing state of the particle-bound bacteria of untreatment surface
By 4mL Tryptic Yeast Extract culture medium is added in each hole, and 37 ℃ of cultivations, with determine antibacterial apply and uncoated surface on the ability of growing.The result shows that the growth on the surface of solids is subjected to the delmopinol applicator and suppresses (table 3).
Table 3
The 4th cell culture Rustless steel Titanium
Uncoated Apply Uncoated Apply
Growth after 1 day Have Do not have Have Do not have
Growth after 5 days Do not have Do not have
In a word, the delmopinol coating surface has significantly reduced the vigor of attached cell, and delmopinol has significantly suppressed the growth of surperficial Related Bacteria.

Claims (22)

1.具有式(I)的化合物或其盐用于防止或减少在表面形成生物被膜或防止或减少活微生物在表面生长的用途，1. Use of a compound of formula (I) or a salt thereof for preventing or reducing the formation of a biofilm on a surface or preventing or reducing the growth of living microorganisms on a surface, 其中R1是位于吗啉环2-或3-位的含8至16个碳原子的直链或支链烷基，R2是含2至10个碳原子的直链或支链烷基，在除α位以外的位置由羟基取代，基团R1和R2的碳原子数总和至少为10，优选为10至20。Wherein R 1 is a straight chain or branched chain alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholine ring, R 2 is a straight chain or branched chain alkyl group containing 2 to 10 carbon atoms, In positions other than the alpha position substituted by hydroxyl groups, the sum of the number of carbon atoms of the groups R1 and R2 is at least 10, preferably 10 to 20. 2.权利要求1的用途，其中所述化合物为地莫匹醇。2. The use according to claim 1, wherein said compound is delmopinol. 3.权利要求1或权利要求2的用途，其中所述表面为医疗设备或形成医疗设备的一部分。3. Use according to claim 1 or claim 2, wherein the surface is or forms part of a medical device. 4.权利要求3的用途，其中所述医疗设备为外科手术植入物。4. The use of claim 3, wherein the medical device is a surgical implant. 5.权利要求1或权利要求2的用途，其中所述表面为接触镜或形成接触镜的一部分。5. The use of claim 1 or claim 2, wherein the surface is or forms part of a contact lens. 6.权利要求1或权利要求2的用途，其中所述表面为流体储存或送递装置。6. The use of claim 1 or claim 2, wherein the surface is a fluid storage or delivery device. 7.权利要求6的用途，其中所述表面为滤器或输水管。7. Use according to claim 6, wherein the surface is a filter or a water pipe. 8.上述权利要求任一项的用途，其中所述表面由所述化合物浸渍或涂覆。8. Use according to any one of the preceding claims, wherein the surface is impregnated or coated with the compound. 9.上述权利要求任一项的用途，其中所述化合物为控释制剂形式，或包含在可控释所述化合物的设备内。9. The use according to any one of the preceding claims, wherein the compound is in the form of a controlled release formulation, or contained within a device which enables the controlled release of the compound. 10.含有具有式(I)的化合物或其盐的材料用于防止在表面形成生物被膜的用途。10. Use of a material comprising a compound of formula (I) or a salt thereof for preventing the formation of biofilms on surfaces. 11.权利要求10的用途，其中所述材料为纺织品。11. Use according to claim 10, wherein the material is a textile. 12.权利要求1的化合物用于在外科手术之前处理手术器具的用途。12. Use of a compound according to claim 1 for the treatment of surgical instruments prior to surgery. 13.由权利要求1的化合物浸渍的药签。13. A swab impregnated with the compound of claim 1. 14.一种医疗设备，其中所述设备由权利要求1的化合物涂覆。14. A medical device, wherein said device is coated with the compound of claim 1. 15.权利要求14的医疗设备，其中所述化合物为地莫匹醇。15. The medical device of claim 14, wherein said compound is delmopinol. 16.权利要求14或权利要求15的医疗设备，其中所述医疗设备为外科手术植入物。16. The medical device of claim 14 or claim 15, wherein the medical device is a surgical implant. 17.权利要求14或15任一项的医疗设备，其中所述设备为接触镜。17. The medical device of any one of claims 14 or 15, wherein the device is a contact lens. 18.权利要求14或15的医疗设备，其中所述设备为牙植入物、导管、支架、导线或整形假体。18. The medical device of claim 14 or 15, wherein the device is a dental implant, catheter, stent, guide wire or orthopedic prosthesis. 19.由权利要求1的化合物涂覆的滤器或输水管。19. A filter or water pipe coated with the compound of claim 1. 20.一种流体储存或流体送递装置，由权利要求1的化合物涂覆。20. A fluid storage or fluid delivery device coated with the compound of claim 1. 21.含有权利要求1或权利要求2的化合物的容器，用于处理表面以防止或减少生物被膜在所述表面形成，或防止或减少活微生物在所述表面生长。21. A container containing a compound of claim 1 or claim 2, for use in treating a surface to prevent or reduce biofilm formation on said surface, or to prevent or reduce the growth of viable microorganisms on said surface. 22.含有多个封闭包装的容器，每个包装含有液体形式的单位剂型的权利要求1或权利要求2的化合物。22. A container comprising a plurality of closed packages, each package containing a compound of claim 1 or claim 2 in a unit dosage form in liquid form.
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